Crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound

ABSTRACT

The invention provides new forms of a chemical compound of formula (I). The invention relates to forms fo a chemical compound (I), in particular to crystalline and amorphous forms, more particularly four crystalline forms and an amorphous form. The invention further relates to processes for the preparation of such forms, to pharmaceutical compositions comprising the compound in crystalline and/or amorphous form and to therapeutic use of such forms.

[0001] The present invention relates to forms of a chemical compound, inparticular to crystalline and amorphous forms, more particularly fourcrystalline forms and an amorphous form. The invention further relatesto processes for the preparation of such forms, to pharmaceuticalcompositions comprising the compound in crystalline and/or amorphousform and to the therapeutic use of such forms.

[0002] In the formulation of drug compositions, it is important for thedrug substance to be in a form in which it can be conveniently handledand processed. This is of importance, not only from the point of view ofobtaining a commercially viable manufacturing process, but also from thepoint of subsequent manufacture of pharmaceutical formulationscomprising the active compound. Chemical stability, solid statestability, and shelf life of the active ingredients are also veryimportant factors. The drug substance, and compositions containing it,should be capable of being effectively stored over appreciable periodsof time, without exhibiting a significant change in the activecomponent's physico-chemical characteristics (e.g. its chemicalcomposition, density, hygroscopicity and solubility). Moreover, it isalso important to be able to provide drug in a form which is as pure aspossible. Amorphous materials may present significant problems in thisregard. For example, such materials are typically more difficult tohandle and to formulate than crystalline material, provide forunreliable solubility, and are often found to be unstable and chemicallyimpure. The skilled person will appreciate that, if a drug can bereadily obtained in a stable crystalline form, the above problems may besolved. Thus, in the manufacture of commercially viable andpharmaceutically acceptable, drug compositions, it is desirable,wherever possible, to provide drug in a substantially crystalline, andstable. form. It is to be noted, however, that this goal is not alwaysachievable. Indeed, typically, it is not possible to predict, frommolecular structure alone, what the crystallisation behaviour of acompound will be, and this can usually only be determined empirically.

[0003] Platelet adhesion and aggregation arc initiating events inarterial thrombosis. Although the process of platelet adhesion to thesub-endothelial surface may have an important role to play in the repairof damaged vessel walls, the platelet aggregation that this initiatescan precipitate acute thrombotic occlusion of vital vascular beds,leading to events with high morbidity such as myocardial infarction andunstable angina The success of interventions used to prevent oralleviate these conditions, such as thrombolysis and angioplasty arealso compromised by platelet-mediated occlusion or re-occlusion.

[0004] It has been found that adenosine 5′-diphosphate (ADP) acts as akey mediator of thrombosis. ADP-induced platelet aggregation is mediatedby the P_(2T) receptor subtype located on the platelet membrane. TheP_(2T) receptor (also known as P2Y_(ADP) or P2T_(AC)) is to primarilyinvolved in mediating platelet aggregation/activation and is a G-proteincoupled receptor which is as yet uncloned. The pharmacologicalcharacteristics of this receptor have been described, for example, inthe references by Humphries et al., Br. J. Pharmacology (1994), 113,1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157-164.Recently it has been shown that antagonists at this receptor offersignificant improvements over other anti-thrombotic agents (see J. Med.Chem. (1999) 42, 213). International Patent Application WO 9905143discloses generically a series of triazolo [4,5-d]pyrimidine compoundshaving activity as P_(2T) (P2Y_(ADP) or P2T_(AC)) antagonists. Thecompound of formula (I) (as depicted below) is embraced by the genericscope of International Patent Application WO 9905143 but is notspecifically disclosed therein. This compound exhibits high potency as aP_(2T) (P²Y_(ADP) or P2T_(AC)) antagonist. It also has a surprisinglyhigh metabolic stability and bioavailibility.

[0005] Accordingly the present invention relates to the compound offormula (I):

[0006] in a substantially crystalline form.

[0007] The compound of formula (I) is conventionally named: {1S-[1α, 2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4difluorophenyl)cyclopropyl[amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol.

[0008] The compound of formula (I) may exist in four differentsubstantially crystalline forms referred to hereafter as Polymorph I,Polymorph II, Polymorph III and Polymorph IV. A polymorph is aparticular crystalline form of a compound.

[0009] The different physical properties of polymorphic forms withrespect to each other and with respect to the amorphous state mayinfluence markedly the chemical and pharmaceutical processing of acompound, particularly when the compound is prepared or used on anindustrial scale.

[0010] In one aspect of the invention, the preferred crystalline form ofthe compound of formula (I) is in the form of Polymorph I, Polymorph II,Polymorph m and/or Polymorph IV.

[0011] In an alternative aspect of the invention, a preferredcrystalline form of the compound of formula (I) is Polymorph I.

[0012] In another aspect of the invention, a preferred crystalline formof the compound of formula (I) is Polymorph II.

[0013] In a further aspect of the invention, a preferred crystallineform of the compound of formula (I) is Polymorph III.

[0014] In an additional aspect of the invention, a preferred crystallineform of the compound of formula (I) is Polymorph IV.

[0015] In a further aspect of the invention, the compound of formula (I)is in a substantially amorphous form. In an amorphous form, the threedimensional long range order that normally exists in a crystalline form(for example in a polymorph) does not exist, and the positions of themolecules relative to one another in the amorphous form are essentiallyrandom (see B. C. Hancock and G. Zografi, J. Pharm. Sci. (1997) 86 1).The amorphous form of the compound of formula (I) is referred to as Formα.

[0016] We have isolated the compound of formula (I) in crystalline andamorphous forms. These forms may exist substantially or essentially freeof water (“anhydrous” forms). Therefore in one aspect of the inventionthere is provided an anhydrous form of the compound of formula (I) in acrystalline form or an amorphous form. By the use of the term“substantially pure and essentially in the anhydrous form”, we do notexclude the presence of some solvent, including water, within thecrystal lattice structure or outside the crystal lattice structure. Ananhydrous form has less than 0.4 water molecules per compound molecule(less than 40% hydrated). Preferably, the anhydrous form contains lessthan 0.1 water molecules per compound molecule.

[0017] Polymorphs I, II, III and IV can be distinguished by reference totheir onset of melting, powder X-ray diffraction patterns and/or singlecrystal X-ray data,

[0018] Polymorph I has an onset of melting which is in the range146-152° C., for example about 151° C., when it is substantially pureand essentially in the anhydrous form.

[0019] Polymorph II has an onset of melting that is in the range136-139° C., for example about 137.5° C., when it is substantially pureand essentially in the anhydrous form.

[0020] Polymorph III has an onset of melting that is in the range127-132° C., for example about 132° C., when it is substantially pureand essentially in the anhydrous form.

[0021] Polymorph IV has an onset of melting which is typically about139° C., when it is substantially pure and essentially in the anhydrousform.

[0022] Form α typically undergoes a glass transition followed bycrystallisation into one of the above Polymorph forms, for examplePolymorph II, prior to melting.

[0023] The melting points were determined using differential scanningcalorimetry (DSC) using Perkin Elmer DSC7 instrumentation. The onset ofmelting is defined as the point at which a significant change from thebaseline occurs and was measured by Perkin Elmer Pyris software. It willbe appreciated that alternative readings of melting point may be givenby other types of equipment or by using conditions different to thosedescribed here. Hence the figures quoted are not to be taken as absolutevalues. The skilled person will realise that the precise value of themelting point will be influenced by the purity of the compound, thesample weight, the heating rate and the particle size.

[0024] Polymorph I, when it is substantially pure and essentially in theanhydrous form, has an X-ray powder diffraction pattern containingspecific peaks of high intensity at 5.3° (±0.1°), 20.1° (±0.1), 20.7°(±0.1°), 21.0° (±0.1°) and 21.3° (±0.1°) 2θ. More preferably,substantially pure and essentially anhydrous Polymorph I has an X-raypowder diffraction pattern containing specific peaks at 5.3° (±0.1°),8.0° (±0.1°), 9.6° (±0.1°), 13.9° (±0.1°), 15.3° (±0.1°), 20.1° (±0.1°), 20.7° (±0.1°), 21.0° (±0.1°), 21.3° (±0.1°), 26.2° (±0.1°) and 27.5°(±0.1°) 2θ.

[0025] Polymorph II, when it is substantially pure and essentially inthe anhydrous form, has an X-ray powder diffraction pattern containingspecific peaks of high intensity at 5.5° (±0.1°), 13.5° (±0.1°), 18.3°(±0.1°), 22.7° (±0.1°) and 24.3° (±0.1°) 2θ. More preferably,substantially pure and essentially anhydrous Polymorph II has an X-raypowder diffraction pattern containing specific peaks at 5.5° (±0.1°),6.8° (±0.1°), 10.6° (±0.1°), 13.5° (±0.1°), 14.9° (±0.1°), 18.3°(±0.1°), 19.2° (±0.1°), 22.7° (±0.1°), 24.3° (±0.1°) and 27.1° (±0.1°)2θ.

[0026] Polymorph III, when it is substantially pure and essentially inthe anhydrous form, has an X-ray powder diffraction pattern containingspecific peaks of high intensity at 14.0° (±0.1°), 17.4° (±0.1°), 18.4°(±0.1°), 21.4° (±0.1°) and 24.1° (±0.1°) 2θ. More preferably,substantially pure and essentially anhydrous Polymorph m has an X-raypowder diffraction pattern containing specific peaks at 5.6° (±0.1°),12.5° (±0.1°), 14.0° (±0.1°), 17.4° (±0.1°), 18.4° (±0.1°), 21.4°(±0.1°), 22.2° (±0.1°), 22.9° (±0.1°), 24.1° (±0.1°) and 24.5° (±0.1°)2θ.

[0027] Polymorph IV, when it is substantially pure and essentially inthe anhydrous form, has an X-ray powder diffraction pattern containingspecific peaks of high intensity at 4.9° (±0.1°), 9.2° (±0.1°), 11.6°(±0.1°), 15.6° (±0.1°) and 16.4° (±0.1°) 2θ. More preferably,substantially pure and essentially anhydrous Polymorph IV has an X-raypowder diffraction pattern containing specific peaks at 4.9° (±0.1°),6.0° (±0.1°), 9.2° (±0.1°), 11.6° (±0.1°), 12.8° (±0.1°), 15.6° (±0.1°),16.4° (±0.1°), 17.2° (±0.1°) and 18.1° (±0.1°) 2θ.

[0028] Form α, when it is substantially pure and essentially in theanhydrous form, has an X-ray powder diffraction pattern containing nosharp peaks.

[0029] The X-ray diffraction data for Polymorph II, Polymorph III,Polymorph IV and Form α. were obtained using Siemens D5000 equipment.The X-ray diffraction data for Polymorph I was obtained using a PhilipsX'Pert MPD machine. It will be appreciated that different equipmentand/or conditions may result in slightly different data being generated.Hence the figures quoted are not to be taken as absolute values.

[0030] In an alternative aspect of the invention, a solvated form may beformed, for example, a hydrated form (a “hydrate”). Therefore in thisaspect of the invention there is provided a hydrate of the compound offormula (I) in crystalline form. A hydrate has 0.8 or more watermolecules per compound molecule (80% or more hydrated). A hemi-hydratehas between 0.4 and 0.8 water molecules per compound molecule (40-80%hydrated).

[0031] In a further feature of the invention there is provided anymixture of crystalline and/or amorphous forms of the compound of formula(I). Preferably, the mixture is of Polymorph I, Polymorph II, PolymorphIII, Polymorph IV and/or Form α. More preferably, the invention providesany mixture of Polymorph II and Polymorph III.

[0032] In a further feature of the invention there is provided a processfor the production of a crystalline form of the compound of formula (I)by crystallisation of the compound of formula (I) from a suitablesolvent. Preferably the solvent is selected from the group: ethanol,ethyl acetate, iso-propanol, iso-octane, acetonitrile, water, or amixture thereof. More preferably, the solvent is selected from thegroup: ethanol, ethyl acetate, iso-propanol, iso-octane, water, or amixture thereof. Suitably, the solvent is selected from the group: amixture of methanol and water, ethanol, ethyl acetate, a mixture ofethanol and water, a mixture of iso-propanol and water, a mixture ofethyl acetate and iso-octane, and acetonitrile.

[0033] The compound of formula (I) can be prepared by methods analogousto those described in WO 9905143.

[0034] To initiate crystallisation, seeding with crystal(s) of thecompound of formula (I) may be required. Seeding with the requiredpolymorph may be necessary to obtain the polymorph of choice.Crystallisation of the compound of formula (I) from an appropriatesolvent system may be achieved by attaining supersaturation, forexample, by cooling, by solvent evaporation and or by the addition of ananti-solvent (a solvent in which the compound of formula (I) is poorlysoluble; examples of suitable anti-solvents include heptane orisooctane). Crystallisation temperatures and times will vary dependingupon the concentration of the compound in solution, the solvent systemused and the method of crystallisation adopted.

[0035] The compound of formula (I) in crystalline form may be isolatedfrom the above reaction mix using techniques well known to those skilledin the art, for example, by decanting, filtration or centrifuging.Similarly the compound of formula (I) in crystalline form may be driedin accordance with well-known procedures.

[0036] Optional recrystallisation step(s) may be performed using thesame or different solvent systems to reduce flier impurities, such asamorphous material, chemical impurities or to convert the crystallineform from one polymorph into another polymorph or into a hydrate or ananhydrous form. In addition a conditioning step may be performed,exposing the solid to high humidity, in order to remove amorphousmaterial.

[0037] Preferably the crystallisation is carried out directly from thereaction solution. Alternatively the crystallisation is performed from asubsequent solution.

[0038] In a further feature of the invention, there is provided aprocess for preparing Polymorph I, which comprises obtaining a few seedcrystals of Polymorph I from the slow crystal growth of Polymorph I froma melt of Polymorph II, and using this to seed a reaction mixturecomprising of the compound of formula (I), and a suitable mixed solventsystem such as methanol/water.

[0039] In a further feature of the invention, there is provided aprocess for preparing Polymorph II, which comprises crystallisation in asuitable solvent such as ethyl acetate.

[0040] In a further feature of the invention, there is provided aprocess for preparing Polymorph III, which comprises crystallisation ina suitable solvent such as an alcohol, for example ethanol or isopropylalcohol (IPA), in particular seeding with crystals of Polymorph m orslurrying a compound of formula (I) in a suitable solvent such as IPA.

[0041] In a further feature of die invention, there is provided aprocess for preparing Polymorph IV, which comprises crystallisation froma suitable solvent such as acetonitrile, in particular seeding withcrystals of Polymorph IV or a period of slurrying a compound of formula(I) in a suitable solvent such as acetonitrile.

[0042] A further feature of the invention provides a process forpreparing Polymorph III substantially free of Polymorph II, whichcomprises, for example, slurrying a compound of formula (I) in C₁₋₆aliphatic alcohol/water solvent system (preferably IPA/water) at atemperature of 5-65° C. for 1-10 days.

[0043] In a further feature of the invention, there is provided aprocess for the production of the compound of formula (I) insubstantially amorphous form which comprises freeze drying or spraydrying a solution of a compound of Formula (I) using a suitable solventsystem, for example ethanol/water.

[0044] The term “substantially free” refers to less than 10% of theother polymorph, preferably less than 5%.

[0045] In a further aspect of the invention, there is provided acompound obtainable by any of the above-mentioned processes.

[0046] The compound of formula (I) in crystalline and/or amorphous formacts as P_(2T) (P2Y_(ADP) or P2T_(AC)) receptor antagonists.Accordingly, the compound of formula (I) in crystalline and/or amorphousform is useful in therapy, including combination therapy. In particular,the compound of formula (I) in crystalline form is indicated for use inthe treatment or prophylaxis of arterial thrombotic complications inpatients with coronary artery, cerebrovascular or peripheral vasculardisease. Arterial thrombotic complications may include unstable angina,primary arterial thrombotic complications of atherosclerosis such asthrombotic or embolic stroke, transient ischaemic attacks, peripheralvascular disease, myocardial infarction with or without thrombolysis,arterial complications due to interventions in atherosclerotic diseasesuch as angioplasty, including coronary angioplasty (PTCA),endarterectomy, stent placement, coronary and other vascular graftsurgery, thrombotic complications of surgical or mechanical damage suchas tissue salvage following accidental or surgical trauma,reconstructive surgery including ski and muscle flaps, conditions with adiffuse thrombotic/platelet consumption component such as disseminatedintravascular coagulation, thrombotic thrombocytopaenic purpura,haemolytic uraemic syndrome, thrombotic complications of septicaemia,adult respiratory distress syndrome, anti-phospholipid syndrome,heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venousthrombosis such as deep vein thrombosis, venoocclusive disease,haematological conditions such as myeloproliferative disease, includingthrombocythaemia, sickle cell disease; or in the prevention ofmechanically-induced platelet activation in vivo, such ascardiopulmonary bypass and extracorporeal membrane oxygenation(prevention of microthromboembolism), mechanically-induced plateletactivation in vitro, such as use in the preservation of blood products,e.g. platelet concentrates, or shunt occlusion such as in renal dialysisand plasmapheresis, thrombosis secondary to vascular damage/inflammationsuch as vasculitis, arteritis, glomerulonephritis, inflammatory boweldisease and organ graft rejection, conditions such as migraine,Raynaud's phenomenon, conditions in which platelets can contribute tothe underlying inflammatory disease process in the vascular wall such asatheromatous plaque formation/progression, stenosis/restenosis and inother inflammatory conditions such as asthma, in which platelets andplatelet-derived factors are implicated in the immunological diseaseprocess. Further indications include treatment of CNS disorders andprevention of the growth and spread of tumours.

[0047] According to a further aspect of the present invention there isprovided a compound of formula (I) in crystalline and/or amorphous formfor use in a method of treatment of the human or animal body by therapy.

[0048] According to an additional feature of the present invention thereis provided the compound of formula (I) in crystalline and/or amorphousform for use as a medicament. Preferably, the compound of formula (I) incrystalline and/or amorphous form is used as a medicament to antagonisethe P_(2T) (P2Y_(ADP) or P2T_(AC)) receptor in a warm-blooded animalsuch as a human being. More preferably, the compound of formula (I) incrystalline and/or amorphous form is used as a medicament for treatingor preventing arterial thrombotic complications in patients withcoronary artery, cerebrovascular or peripheral vascular disease in awarm-blooded animal such as a human being.

[0049] According to the invention there is further provided the use ofthe compound of formula (I) in crystalline and/or amorphous form in themanufacture of a medicament for use as an antagonist of the P_(2T)(P2Y_(ADP) or P2T_(AC)) receptor. In particular there is furtherprovided the use of the compound of formula (I) in crystalline and/oramorphous form in the manufacture of a medicament for use in thetreatment or prevention of arterial thrombotic complications in patientswith coronary artery, cerebrovascular or peripheral vascular disease.

[0050] The invention also provides a method of treatment or preventionof arterial thrombotic complications in patients with coronary artery,cerebrovascular or peripheral vascular disease, which comprisesadministering to a person suffering from or susceptible to such adisorder a therapeutically effective amount of the compound of formula(I) in crystalline and/or amorphous form.

[0051] The compound of formula (I) in crystalline and/or amorphous formmay be administered topically, e.g. to the lung and/or the airways, inthe form of solutions, suspensions, HFA aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, pills, capsules, syrups, powders or granules, or byparenteral administration in the form of sterile parenteral solutions orsuspensions, by subcutaneous administration, or by rectal administrationin the form of suppositories or transdermally.

[0052] The compound of formula (I) in crystalline and/or amorphous formmay be administered on its own or as a pharmaceutical compositioncomprising the compound of formula (I) in crystalline and/or amorphousform in combination with a pharmaceutically acceptable diluent, adjuvantand/or carrier. Therefore there is provided as a further feature of theinvention a pharmaceutical composition comprising the compound offormula (I) in crystalline and/or amorphous form in association with apharmaceutically acceptable diluent, adjuvant and/or carrier.Particularly preferred are compositions not containing material capableof causing an adverse reaction, such as an adverse allergic reaction.

[0053] Dry powder formulations and pressurised HFA aerosols of thecompound of formula (I) in crystalline and/or amorphous form may beadministered by oral or nasal inhalation. For inhalation the compound offormula (I) in crystalline and/or amorphous form is desirably finelydivided. The compound of formula (I) in crystalline and/or amorphousform may also be administered by means of a dry powder inhaler. Theinhaler may be a single or a multi dose inhaler, and may be a breathactuated dry powder inhaler.

[0054] One possibility is to mix the finely divided compound of formula(I) in crystalline and/or amorphous form with a carrier substance, e.g.a mono-, di- or polysaccharide, a sugar alcohol or another polyol.Suitable carriers include sugars and starch. Alternatively the finelydivided compound of formula (I) in crystalline and/or amorphous form maybe coated by another substance. The powder mixture may also be dispensedinto hard gelatine capsules, each containing the desired dose of theactive compound of formula (I) in crystalline and/or amorphous form.

[0055] Another possibility is to process the finely divided powder intospheres which break up during the inhalation procedure. This spheronizedpowder may be filled into the drug reservoir of a multidose inhaler,e.g. that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive compound of formula (I) with or without a carrier substance isdelivered to the patient. The pharmaceutical composition comprising thecompound of formula (I) in crystalline and/or amorphous form mayconveniently be tablets, pills, capsules, syrups, powders or granulesfor oral administration; sterile parenteral or subcutaneous solutions,suspensions for parenteral administration or suppositories for rectaladministration.

[0056] For oral administration the compound of formula (I) incrystalline and/or amorphous form may be admixed with an adjuvant or acarrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such aspotato starch, corn starch or amylopectin, cellulose derivatives, abinder such as gelatine or polyvinylpyrrolidone, and a lubricant such asmagnesium stearate, calcium stearate, polyethylene glycol, waxes,paraffin, and the like, and then compressed into tablets. If coatedtablets are required, the cores, prepared as described above, may becoated with a concentrated sugar solution which may contain e.g. gumarabic, gelatine, talcum, titanium dioxide, and the like. Alternatively,the tablet may be coated with a suitable polymer dissolved either in areadily volatile organic solvent or an aqueous solvent.

[0057] For the preparation of soft gelatine capsules, the compound offormula (I) in crystalline and/or amorphous form may be admixed withe.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules maycontain granules of the compound using either the above mentionedexcipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol,starches, cellulose derivatives or gelatine. Also liquid or semisolidformulations of the drug may be filled into hard gelatine capsules.

[0058] Liquid preparations for oral application may be in the form ofsyrups or suspensions, for example solutions containing the compound offormula (I) in crystalline and/or amorphous form, the balance beingsugar and a mixture of ethanol, water, glycerol and propylene glycol.Optionally such liquid preparations may contain colouring agents,flavouring agents, saccharine and carboxymethylcellulose as a thickeningagent or other excipients known to those skilled in art.

[0059]FIG. 1.1 is an X-ray diffraction pattern for Polymorph I wasobtained using a Philips X'Pert MPD machine in θ-θ configuration overthe scan range 1° to 40° 2θ with 2 or 5 seconds exposure per 0.02° 2θincrement. The X-rays were generated by a copper long-fine focus tubeoperated at 40 kV and 50 mA. The wavelength of the X-rays was 1.5406 Å.

[0060] FIG. 1.2 is an X-ray diffraction pattern for Polymorph IIobtained using a Siemens D5000 machine in θ-θ configuration over thescan range 2° to 30° 2θ with 4 seconds exposure per 0.02° 2θ increment.The X-rays were generated by a copper long-fine focus tube operated at45 kV and 40 mA. The wavelength of the X-rays was 1.5406 Å. Data werecollected using a zero background on which˜10 mg of the compound wasplaced. The holder was made from a single crystal of silicon, which hadbeen cut along a non-diffracting plane and then polished to an opticallyflat finish The X-rays incident upon this surface were negated by Braggextinction.

[0061]FIG. 1.3 is an X-ray diffraction pattern for Polymorphs m obtainedusing a Siemens D5000 machine as described above.

[0062]FIG. 1.4 is an X-ray diffraction pattern for Polymorphs IVobtained using a Siemens D5000 machine as described above.

[0063]FIG. 1.5 is an X-ray diffraction pattern for Form a obtained usinga Siemens D5000 machine as described above.

[0064]FIG. 2 shows DSC graphs for Polymorph I, II, III and IV and Form aobtained using a Perkin Elmer DSC 7 instrument. The pan type wasaluminium with a pierced lid. The sample weight was 1 to 3 mg. Theprocedure was carried out under a flow of nitrogen gas (30 ml/min) andthe temperature range studied was 30° C. to 325° C. at a constant rateof temperature increase of 10° C. per minute.

[0065] It should be realised that analysis of samples with grains above30 microns in size and non-unitary aspect ratios may affect the relativeintensity of peaks. The skilled person will also realise that theposition of reflections is affected by the precise height at which thesample sits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values.

[0066] The invention may be illustrated by the following non-limitingExamples.

EXAMPLE 1{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diolin the Form of Polymorph I

[0067] Part 1

[0068] The compound of formula (I) in the form of Polymorph II (2 mg)was heated and cooled in a DSC in the following way: 35 to 143 to 35 to148 to 35 to 148 to 35° C. This annealing process resulted in thecrystallisation of pure Polymorph I as indicated by DSC.

[0069] Part 2

[0070] A solution comprising of the compound of formula (I), 5 ml/gmethanol and 7.3 ml/g water and a small quantity of seeds of PolymorphI, was crystallised at 30° C. XRPD and DSC confirmed that substantiallypure Polymorph I had been formed.

EXAMPLE 2{1S-1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diolin the form of Polymorph II

[0071] Chloroform (150 μl) was added to 45 mg of the compound of formula(I) and the mixture was warmed to dissolution over a steam bath. Theresulting solution was left to crystallise over night and dried underflowing nitrogen. XRPD and DSC confirmed that substantially purePolymorph II had been formed.

EXAMPLE 3{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diolin the Form of Polymorph III

[0072] Ethanol (200 μl) was added to 10 mg of the compound of formula(I) and the mixture warmed to dissolution over a steam bath. Theresulting solution was left to crystallise over night. XRPD and DSCconfirmed that a mixture of Polymorphs II and III had been formed. Thismaterial was used to seed a larger scale preparation: 191 mg ofPolymorph II were slurried in 1 ml of a 50% aqueous solution ofisopropanol. To this slurry, 15 mg of seeds of mixed Polymorph II/IIIwere added. After 2 days complete conversion into Polymorph III hadoccurred as shown by XRPD.

EXAMPLE 4 {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diolin the Form of Polymorph IV

[0073] Acetonitrile (0.12 ml) was added to 10mg of the compound offormula (I) and the mixture warmed to dissolution over a steam bath. Thewarm solution was allowed to cool slowly in a water jacket of hot water.The resulting crystals were dried under nitrogen. XRPD indicated thatthis was a distinct polymorph.

EXAMPLE 5{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diolPredominently in the Form of Form α.

[0074] The compound of formula (I) (218 mg) was dissolved in a 50%aqueous solution of ethanol (24 ml). To this solution, a further 14.5 mlof water were added dropwise. The resulting saturated solution was thenfreeze dried using Virtis instrumentation under the following conditions(vacuum 2170 mT, run time 20.2 hours, condensed temperature −52° C.,ambient temperature 20.3° C.).

REFERENCE EXAMPLE 1 {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(34-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol

[0075] A solution of{3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4yl)oxy]ethanol(Method A, 0.59 g) in trifluoroacetic acid (15 ml) and water(15 ml) wasstirred at room temperature for 30 minutes. The reaction mixture wascarefully added to a solution of sodium bicarbonate (21 g) in water (150ml) and stirred for 30 minutes. The mixture was extracted with ethylacetate, which was dried and evaporated. The residue was purified (SiO₂,ethyl acetate as eluent) to afford the title compound (0.44 g). MS(APCI) 523 M+W⁺, 100%); NMR: 8.95 (1H, d, J=3.3), 7.39-7.21 (2H, m),7.10-7.00 (1H, m), 5.12 (1H, d, J=6.4), 5.05 (1H, d, J=3.6), 4.96 (1H,q, J=9.0), 4.62-4.54 (2H, m), 3.95 (1H, br s), 3.79-3.73 (1H, m),3.55-3.47 (4H, m), 3.20-3.13 (1H, m), 2.98-2.81 (2H, m), 2.63 (1H, dt,J=13.6, 8.5), 2.29-2.21 and 2.16-2.09 (1H, m), 2.07-2.00 (1H, m),1.73-1.33 (4H, m), 0.99 (3H, t, J=7.4).

[0076] Preparation of Starting Materials

[0077] The starting materials are either commercially available or arereadily prepared by standard methods from known materials. For examplethe following reactions are illustrations but not limitations of thepreparation of some of the starting materials used in the abovereactions.

[0078] Method A

{3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4Difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy]ethanol

[0079] DIBAL-H® (1.0M solution in hexanes, 5.15 ml) was added to anice-cooled solution of {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-{[6-(7-{[2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy}acetic acid, methyl ester (Method B, 0.76 g) in THF (1 ml) and thesolution was stirred at this temperature for 2 hours. The reactionmixture was concentrated in vacuo and the residue was dissolved in ethylacetate (75 ml). A saturated aqueous solution of sodium potassiumtartrate (75 ml) was added and the mixture stirred vigorously for 16hours. The organics were collected and the aqueous re-extracted withethyl acetate (2×50 ml). The combined organics were dried andconcentrated and the residue purified (SiO₂, isohexane:ethylacetate 1:1as eluant) to give the title compound (0.63 g). MS (APCI) 563 (M+H³⁰,100%).

[0080] Method B

{3aR-[3aα,4α,6α(1R*,2S*),6aα]}-{[6-(7-{[2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4yl]oxy}aceticacid, methyl ester

[0081] To a mixture of[3aR-(3aα,4α,6α,6aα)]-({6-[7-bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol}oxy)aceticacid, methyl ester (Method D, 0.80 g) and(1R-trans)-2-(3,4-difluorophenyl)cyclopropanamine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (Method C,0.61 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine(0.85 ml). The resulting solution was stirred at room temperature for 16hours then concentrated in vacuo. Purification (SiO₂,isohexane:ethylacetate 3:1 as eluant) gave the title compound as acolourless foam (0.77 g). MS (APCI) 591 (M+H⁺, 100%).

[0082] Method C

(1R-trans)-2-(3,4-Difluorophenyl)cyclopropananine,[R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1)

[0083] The title compound may be prepared according to the proceduredescribed in WO 9905143.

[0084] Method D

[3aR-(3aα,4α,6α,6aα)]-({6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol}oxy)aceticacid, Methyl Ester

[0085][3aR-(3aα,4α,6α,6aα)]-({6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol}oxy)aceticacid, methyl ester (Method E, 1.1 g) and isoamylnitrite (2.4 ml) inbromoform (30 ml) was heated at 80° C. for 30 minutes. The cooledreaction mixture was purified (SiO₂, ethyl acetate:isohexane 1:4 aseluent) to afford the title compound (0.44 g). MS (APCI) 502/4 (M+H⁺),504 (100%).

[0086] Method E

[3a,R-(3aα,4α,6α,6aα)]-({6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol}oxy)aceticacid, Methyl Ester

[0087] To a solution of[3aR(3aα,4α,6α,6aα)]-6-(7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol(Method F, 0.50 g) in TBF (25 ml) at 0° C., was added butyllithium (0.62ml of 2.5N in hexanes). After 20 minutes, the suspension was treatedwith a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester(0.34 g) (prepared according to the method of Biton, Tetrahedron, 1995,51, 10513) in THF (10 ml). The resulting solution was allowed to warm toroom temperature then concentrated and purified (SiO₂, ethyl acetate:hexane 4:6 as eluant) to afford the title compound (0.25 g). MS (APCI)439 (M+H⁺, 100%).

[0088] Method F

[3aR-(3aα,4α,6α,6aα)]-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0089][3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol(Method G, 13.2 g) in THF (200 ml) containing 0.88 ammonia (5 ml) wasstirred for 2 hours then concentrated to dryness and the residuepartitioned between water and ethyl acetate. The organics were dried andthen concentrated to afford the title compound (12.5 g). MS (APCI) 367(M+H⁺, 100%).

[0090] Method G

[3aR-(3aα,4α,6α,6aα)]-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4.5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0091] Isoamyl nitrite (1.1 ml) was added to a solution of [3aR-(3aα,4α,,6α,6aα)]-6-{[5-amino-6-Chloro-2-(propylthio)pyrimidin-4-yl]amino}-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol(Method H, 2.0 g) in acetonitrile (100 ml) and the solution was heatedat 70° C. for 1 hour. The cooled reaction mixture was concentrated andpurified (SiO₂, ethyl acetate:isohexane 1:3 as eluant) to afford thetitle compound (1.9 g). MS (APCI) 386 (M+H⁺, 100%).

[0092] Method H

[3aR-(3aα,4α,6α,6aα)]-6-{[5-Amino-6-Chloro-2-(propylthio)pyrimidin-4-yl]amino}-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0093] Iron powder (3.0 g) was added to a stirred solution of[3aR-(3aα,4α,6α,6aα)]-6-{[6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl]amino}tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol (Method I, 2.7 g) in acetic acid(100 ml). The reaction mixture was stirred at room temperature for 2hours, concentrated to half volume, diluted with ethyl acetate andwashed with water. The organic phase was dried and concentrated toafford the title compound (2.0 g). MS (APCI) 375 (M+H⁺, 100%).

[0094] Method I

[3aR-(3aα,4α,6α,6aα)]-6-{[6-Choro-5-nitro-2-(propylthio)pyrimidin-4-yl]amino}tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol

[0095] A solution of[3aR-(3aα,4α,6α,6aα)]-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,hydrochloride (Method J, 10.0 g) and N,N-diisopropylethylamine (35 ml)in THF (600 ml) was stirred for 1 hour. The mixture was filtered and thesolution was added over 1 hour to a solution of4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (WO 9703084, 25 .6 g) inTHF (1000 ml) and stirred for a further 2 hours. The solvent volume wasreduced in vacuo and ethyl acetate was added (1000 ml). The mixture waswashed with water and the organic layers were dried, evaporated andpurified (SiO₂, isohexane-ethyl acetate as eluant) to afford the titlecompound (14.2 g). MS (APCI) 405 (M+H⁺, 100%).

[0096] Method J

[3aR-(3aα,4α,6α,6aα)]-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol,Hydrochloride[1R-(1α,2β,3β,4α)]-2,3,4-Trihydroxycyclopentenylimidodicarbonic acid,bis(1,1-dimethylethyl) ester (Method K, 17.4 g) in 6M HCl (100ml)/methanol (500 ml) was stirred for 18 hours. The mixture wasevaporated and then azeotroped with toluene (4×200 ml) to give acolourless powder (8.7 g). This solid was suspended in acetone (250 ml)containing 2,2-dimethoxypropane (25 ml) and conc. HCl (0.2 ml) thenheated under reflex for 2 hours. The mixture was cooled, evaporated andazeotroped with toluene (3×200 ml). The residue was dissolved in 20%aqueous acetic acid and stirred for 2 hours. The mixture was evaporatedand azeotroped with toluene (4×200 ml) to afford the title compound(10.1 g). MS (APCI) 174 (M+H⁺, 100%)

[0097] Method K

[1R-(1α,2β,3β,4α]-2,3,4-Trihydroxycyclopentenylimidodicarbonic acid,bis(1,1-dimethylethyl) ester

[0098] To a solution of(1R-cis)-Bis(1,1-dimethylethyl)-4hydroxy-2-cyclopentenylimido-dicarbonate(Method L, 17.1 g) in THF (500 ml)/water (50 ml) was addedN-methylmorpholine-N-oxide (9.4 g) followed by osmium tetroxide (10 ml,2.5% solution in t-butanol). The mixture was stirred at room temperaturefor 4 days then treated with sodium hydrosulphite (6.0 g). Thesuspension was filtered through diatomaceous earth and the productpurified (SiO₂, ethyl acetate: hexane 1:1 as eluant) to afford the titlecompound (19.1 g). NMR: 1.44 (18H, s), 1.46-1.60 (1H, m), 1.97-2.05 (1H,m), 3.55-3.58 (1H, m), 3.66-3.73 (1H, m), 4.11-4.21 (2H, m), 4.54 (1H,d,J=4.8), 4.56 (1H, d,J=5.9), 4.82 (1H, d, J=4.6).

[0099] Method L

(1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate

[0100] To a suspension of ether washed sodium hydride (60% dispersion inoil; 0.31 g) in THF (30 ml) was added imidodicarbonic acidbis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40° C.for 1 hour. To the mixture, at ambient temperature, was then added(1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) andtetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixturewas stirred for 24 hours then purified (SiO₂, ethyl acetate: hexane 1:9as eluant) to give the title compound as a colourless solid (0.90 g).NMR: 1.43 (18H, s), 1.61 (1H, ddd, J=12.3, 7.7, 6.4), 2.54 (1H, dt,J=12.6, 7.4), 4.51-4.57 (1H, m), 4.86 (1H, tq, J=8.0, 1.8), 4.91 (1H, d,J=5.4), 5.71-5.77 (2H, m).

EXAMPLE 2

[0101] The following illustrate representative pharmaceutical dosageforms containing the compound of formula (I) in crystalline and/oramorphous form (hereafter compound X), for therapeutic or prophylacticuse in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur182.75 Croscarmellose sodium  12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate  3.0 (b) Tablet II mg/tablet Compound X  50Lactose Ph.Eur 223.75 Croscarmellose sodium  6.0 Maize starch  15.0Polyvinylpyrrolidone (5% w/v paste)  2.25 Magnesium stearate  3.0 (c)Tablet III mg/tablet Compound X  1.0 Lactose Ph.Eur  93.25Croscarmellose sodium  4.0 Maize starch paste (5% w/v paste)  0.75Magnesium stearate  1.0 (d) Capsule mg/capsule Compound X  10 LactosePh.Eur 488.5 Magnesium stearate  1.5 (e) Injection I (50 mg/ml) CompoundX  5.0% w/v 1N Sodium hydroxide solution 15.0% v/v 0.1N Hydrochloricacid (to adjust pH to 7.6) Polyethylene glycol 400  4.5% w/v Water forinjection to 100% (f) Injection II (10 mg/ml) Compound X  1.0% w/vSodium phosphate BP  3.6% w/v 0.1N Sodium hydroxide solution 15.0% v/vWater for injection to 100% (g) Injection III (1 mg/ml, buffered to pH6)Compound X  0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/vPolyethylene glycol 400  3.5% w/v Water for injection to 100%

[0102] NMR spectra were measured on a Varian Unity Inova 300 or 400spectrometer; NMR data is quoted in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard using perdeuteriodimethyl sulphoxide (DMSO-δ₆) as solvent unless otherwise indicated; forexamples which showed the presence of rotamers in the proton NMR spectraonly the chemical shifts of the major rotamer are quoted; couplingconstants (J) are given in Hz.

[0103] Mass Spectra (MS) were measured as follows: EI spectra wereobtained on a VG70-250S or Finnigan Mat Incos-XL spectrometer, FABspectra were obtained on a VG70-250SEQ spectrometer, ESI and APCIspectra were obtained on Finnigan Mat SSQ7000 or a Micromass Platformspectrometer.

[0104] Preparative RPLC separadoizs were generally performed using aNovapak®, Bondapak® or Hypersil® column packed with BDSC-18 reversephase silica

[0105] Flash chromatography (indicated in the Examples as (SiO₂)) wascarried out using Fisher Matrix silica, 35-70 μm.

[0106] Abbreviations THF tetrahydrofuran XRPD X-ray Powder DiffractionDSC Differential scanning calorimetry

1. A compound of formula (I):

in a substantially crystalline form.
 2. A compound of formula (I) asclaimed in claim 1 that exists in a substantially anhydrous form.
 3. Acompound of formula (I) as claimed in claim 1, characterised by an X-raypowder diffraction pattern containing specific peaks of high intensityat 5.3° (±0.1°), 20.1° (±0.1°), 20.7° (±0.1°), 21.0° (±0.1°) and 21.3°(±0.1°) 2θ.
 4. A compound of formula (I) as claimed in claim 1 or 3,characterised by an X-ray powder diffraction pattern containing specificpeaks at 5.3° (±0.1°), 8.0° (±0.1°), 9.6° (±0.1°), 13.9° (±0.1°), 15.3°(±0.1°), 20.1° (±0.1), 20.7° (±0.1°), 21.0° (±0.1°), 21.3° (±0.1°),26.2° (±0.1°) and 27.5° (±0.1°) 2θ.
 5. A compound of formula (I) asclaimed in any one of claims 1, 3 or 4, characterised by a differentialscanning calorimetry curve to have an onset of melting which is in therange 146-152° C.
 6. A compound of formula (I) as claimed in claim 1,characterised by an X-ray powder diffraction pattern containing specificpeaks of high intensity at 5.5° (±0.1°), 13.5° (±0.1°), 18.3° (±0.1°),22.7° (±0.1°) and 24.3° (±0.1°) 2θ.
 7. A compound of formula (I) asclaimed in claim 1 or 6, characterised by an X-ray powder diffractionpattern containing specific peaks at 5.5° (±0.1°), 6.8° (±0.1°), 10.6°(±0.1°), 13.5° (±0.1°), 14.9° (±0.1°), 18.3° (±0.1°), 19.2° (±0.1°),22.7° (±0.1°), 24.3° (±0.1°) and 27.1° (±0.1°) 2θ.
 8. A compound offormula (I) as claimed in any one of claims 1 to 6 or 7 characterised bya differential scanning calorimetry curve to have an onset of meltingwhich is in the range 136-139° C.
 9. A compound of formula (I) asclaimed in claim 1, characterised by an X-ray powder diffraction patterncontaining specific peaks of high intensity at 14.0° (±0.1°), 17.4°(±0.1°), 18.4° (±0.1°), 21.4° (±0.1°) and 24.1°(±0.1°) 2θ.
 10. Acompound of formula (I) as claimed in claims 1 or 9, characterised by anX-ray powder diffraction pattern containing specific peaks at 5.6°(±0.1°), 12.5° (±0.1°), 14.0° (±0.1°), 17.4° (±0.1°), 18.4° (±0.1°),21.4° (±0.1°), 22.2° (±0.1°), 22.9° (±0.1°), 24.1° (±0.1°) and 24.5°(±0.1) 2θ.
 11. A compound of formula (I) as claimed in any one of claims1, 9 or 10 characterised by a differential scanning calorimetry curve tohave an onset of melting which is in the range 127-132° C.
 12. Acompound of formula (I) as claimed in claim 1, characterised by an X-raypowder diffraction pattern containing specific peaks of high intensityat 4.9° (±0.1°), 9.2° (±0.1°), 11.6° (±0.1°), 15.6° (±0.1°) and 16.4°(±0.1°) 2θ.
 13. A compound of formula (I) as claimed in claim 1 or 12characterised by an X-ray powder diffraction pattern containing specificpeaks at 4.9° (±0.1°), 6.0° (±0.1°), 9.2° (±0.1°), 11.6° (±0.1°), 12.8°(±0.1°), 15.6° (±0.1°), 16.4° (±0.1°), 17.2° (±0.1°) and 18.1°
 14. Acompound of formula (I) as claimed in any one of claims 1, 12 or 13characterised by a differential scanning calorimetry curve to have anonset of melting which at approximately 139° C.
 15. A compound offormula (I) in a substantially amorphous form.
 16. A compound of formula(I) which is in the form of a hydrate.
 17. A mixture of a compound offormula (I) as claimed in any one of claims 6 to 8 and a compound offormula (I) as claimed in any one of claims 9 to
 11. 18. A process forthe preparation of a compound as claimed in claim 1, wherein thecompound of formula (I) is crystallised from a solvent selected from thegroup: lower alkyl acetates, lower alkyl alcohols, aliphatic andaromatic hydrocarbons, dialkyl ethers, dialkyl ketones, acetonitrile,water, or a mixture thereof.
 19. A process as claimed in claim 18,wherein the solvent is selected from the group: ethanol, ethyl acetate,iso-propanol, iso-octane, acetonitrile, water, or a mixture thereof. 20.A process as claimed in claim 19, wherein the solvent is selected fromthe group: a mixture of methanol and water, ethanol, ethyl acetate, amixture of ethanol and water, a mixture of iso-propanol and water, amixture of ethyl acetate and iso-octane, and acetonitrile.
 21. A processfor the production of a compound as claimed in any one of claims 3 to 5according to any one of claims 18 to 20 in which the solvent is amixture of methanol and water.
 22. A process for the production of acompound as claimed in any one of claims 3 to 5 using seed.
 23. Aprocess according to claim 22 in which the seed is prepared by melting acompound as claimed in any one of claims 6 to
 8. 24. A process for theproduction of a compound as claimed in any one of claims 6 to 8according to any one of claims 18 to 20, in which the solvent is ethylacetate.
 25. A process for the production of a compound as claimed inany one of claims 9 to 11 according to any one of claims 18 to 20, inwhich the solvent is an alcohol.
 26. A process for the production of acompound as claimed in any one of claims 9 to 11 which comprisesslurrying a compound of formula (I) in IPA/water solvent system at atemperature of 5 to 65° C.
 27. A process for the production of acompound as claimed in any one of claims 12 to 14, which comprises aprocess according to any one of claims 18 to 20, in which the solvent isacetonitrile.
 28. A compound as claimed in any one of claims 1 to 17 foruse as a medicament
 29. A pharmaceutical composition comprising acompound as claimed in any one of claims 1 to 17 in admixture with apharmaceutically acceptable adjuvant, diluent or carrier.
 30. Apharmaceutical composition comprising a compound as claimed in any oneof claims 1 to 17 for use in the prevention of arterial thromboticcomplications in patients with coronary artery, cerebrovascular orperipheral vascular disease.
 31. The use of a compound as claimed in anyone of claims 1 to 17 in the manufacture of a medicament for use in theprevention of arterial thrombotic complications in patients withcoronary artery, cerebrovascular or peripheral vascular disease.
 32. Amethod of treatment or prevention of arterial thrombotic complicationsin patients with coronary artery, cerebrovascular or peripheral vasculardisease, which comprises administering to a person suffering from orsusceptible to such a disorder a therapeutically effective amount of acompound as claimed in any one of claims 1 to 17.